Gangaraju Radhika, Song Jihyun, Kim Soo Jin, Tashi Tsewang, Reeves Brandi N, Sundar Krishna M, Thiagarajan Perumal, Prchal Josef T
Division of Hematology-Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL.
Division of Hematology, School of Medicine, University of Utah, Salt Lake City, UT.
Blood Adv. 2020 Mar 24;4(6):1115-1130. doi: 10.1182/bloodadvances.2019001379.
Thrombosis is a major cause of morbidity and mortality in polycythemia vera (PV) and essential thrombocythemia (ET). The pathophysiology of thrombosis in these disorders remains unclear, and we hypothesized that upregulation of thrombotic, inflammatory, and hypoxia-inducible factor (HIF)-regulated genes may play a role in it. We performed unbiased RNA sequencing in granulocytes and platelets of PV patients and found differential expression of several thrombotic, inflammatory, and HIF-regulated genes. The expression of many of these genes positively correlated with JAK2 expression and JAK2V617F allelic burden. We then validated these findings by quantitative polymerase chain reaction analyses of selected gene transcripts in a larger number of PV and ET granulocytes and platelets (58 patients) and in 28 controls, and we compared these findings in patients with and without thrombosis. The study included 29 females and 29 males; of these, 28 had a history of thrombosis. We found that transcripts of several selected genes were upregulated in patients with PV or ET compared with controls. In granulocytes, the expression levels of F3, SELP, VEGFA, and SLC2A1 were significantly higher in patients with a history of thrombosis compared with those who did not have thrombosis. Patients with a history of thrombosis have significantly higher expression of IL1RAP (P < .05) in platelets compared with those without thrombosis. Our study confirms the presence of a thrombo-inflammatory state and augmented HIF activity in PV and ET and its role in thrombosis. These data may provide the background for targeted therapies in PV and ET.
血栓形成是真性红细胞增多症（PV）和原发性血小板增多症（ET）发病和死亡的主要原因。这些疾病中血栓形成的病理生理学仍不清楚，我们推测血栓形成、炎症和缺氧诱导因子（HIF）调节基因的上调可能在其中起作用。我们对PV患者的粒细胞和血小板进行了无偏倚RNA测序，发现了几种血栓形成、炎症和HIF调节基因的差异表达。这些基因中的许多基因表达与JAK2表达和JAK2V617F等位基因负荷呈正相关。然后，我们通过定量聚合酶链反应分析对更多PV和ET粒细胞及血小板（58例患者）以及28例对照中选定基因转录本进行验证，并比较了有或无血栓形成患者的这些结果。该研究包括29名女性和29名男性；其中28例有血栓形成史。我们发现，与对照组相比，PV或ET患者中几种选定基因的转录本上调。在粒细胞中，有血栓形成史的患者与无血栓形成史的患者相比，F3、SELP、VEGFA和SLC2A1的表达水平显著更高。有血栓形成史的患者与无血栓形成史的患者相比，血小板中IL1RAP的表达显著更高（P <.05）。我们的研究证实了PV和ET中存在血栓炎症状态和增强的HIF活性及其在血栓形成中的作用。这些数据可能为PV和ET的靶向治疗提供背景。
